Apoptosis, or programmed cell death, is controlled by the B-cell lymphoma 2 (BCL-2) family of cellular proteins, which contains both pro-apoptotic (e.g. BAK, BAX, BIM and NOXA) and anti-apoptotic (e.g. BCL-2, BCL-XL and MCL-1) members. The pro-apoptotic members can be further divided into the BCL-2 effectors (BAK, BAX), multi-BH domain proteins located within the mitochondria membrane, and the BH3-only activators (BID, NOXA), proteins that solely express the α-helical BH3 domain of the effector proteins. Under homeostatic conditions, the effector proteins’ α-helical BH3 domain interacts with the hydrophobic binding groove on the surface of the anti-apoptotic proteins, capturing the effector proteins and blocking apoptosis. Once a cell is exposed to apoptotic stress, it expresses the BH3-only activator proteins which release the effector proteins from sequestration to initiate apoptosis. Various human cancers exploit this pathway by upregulating the expression of the anti-apoptotic proteins, resulting in the capture of the BH3-only proteins before they can release the effector proteins, thus inhibiting apoptosis. A current strategy deployed to combat this oncogenic transformation is BH3 mimicry, that is the development of small molecules that can mimic the α-helical BH3 domain and thereby free up the native BH3-only proteins to initiate apoptosis. BH3 mimetics have shown promising activity in clinical studies. Indeed, ABT-199, a selective BH3 mimetic for BCL-2, has recently been approved by the FDA for chronic lymphocytic leukemia. Unfortunately, resistance has been observed in cancer cells exposed to ABT-199, manifested by the upregulation of MCL-1 as a compensatory mechanism to counter BCL-2 inhibition. Hence, to overcome the resistance mechanism associated with ABT-199 and to avoid thrombocytopenia, which is a known consequence of BCL-XL inhibition in platelets, we will report our progress towards the development of dual MCL-1/BCL-2 inhibitors via a hybridization strategy between fragments of potent MCL-1 and BCL-2 inhibitors.

Dual inhibition of the oncoproteins MCL-1 and BCL-2 by rationally designed polypharmacology

254th National Meeting (2017)

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